It is now well established that the potential of Magnetic Resonance Imaging (MRI) procedures can be further enhanced when this diagnostic modality is applied in conjunction with the administration of contrast agents (CAs), i.e. chemicals able to promote marked changes in the relaxation rates of the tissue protons. The MRI CAs are principally represented by paramagnetic complexes, mostly containing Gd(III), Fe(III) or Mn(II) ions, which affect the relaxation rates of the bulk water through the exchange of the water molecules in their coordination spheres (Caravan P, et al. Chem Rev 1999, 99:2293-2352; the Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging. Chichester, UK: John Wiley & Sons; 2001. p 45-120).
The efficacy of a paramagnetic complex is assessed by its proton relaxation enhancement or relaxivity (ri, i=1, 2), which represents the increase of the proton relaxation rate of an aqueous solution containing 1 mM concentration of the paramagnetic agent in comparison to the proton relaxation rate of neat water. For a paramagnetic complex, the proton relaxation enhancement is chiefly governed by the choice of the paramagnetic metal, the rotational correlation time of the complex and the accessibility of the metal to the surrounding water molecules, i.e. the rapid exchange of water with the bulk.
Two characteristic relaxation rates are involved: R1 that is defined as the inverse of the longitudinal relaxation time or spin lattice relaxation time T1, i.e. 1/T1, and R2 that is defined as the inverse of the transverse relaxation time or spin-spin relaxation time T2, i.e. 1/T2.
The higher the longitudinal relaxivity (r1), the larger is the signal enhancement detected in the corresponding T1-weighted MR images and the better is the contrast differentiation in the resulting images.
Some contrast agents exist which relaxivity is related to and may depend upon the physical or chemical characteristics of the microenvironment in which they distribute. These agents are known as responsive agents because the contrast, in the image they promote, is responsive to a physical or chemical parameter of diagnostic interest. Several systems have been reported which relaxivity is made dependent on pH, temperature, PO2, enzymatic activity, ion and metabolite concentrations (Jacques V, Top Curr Chem 2002, 221, 123-164).
However, such a peculiar responsive property could not have been properly exploited in practice because the detected T1-variations cannot be unambiguously ascribed to a change in relaxivity and, consequently, to a variation on the physical or chemical parameter under examination, if the actual concentration of the paramagnetic complex is unknown. To be effective, a MRI responsive agent should display its responsiveness in a concentration independent mode. Accordingly, it is an object of the present invention a MRI method and agents allowing the overcoming of this drawback.